The first two years of the proposed work will be spent investigating phencyclidine (PCP) effects in rats as a heuristic model for idiopathic psychosis in humans. In vivo intracerebral microdialysis will be used to examine the effects of PCP, and of selected PCP receptor agonists and direct N-methyl-D-aspartate (NMDA) receptor antagonists on extracellular concentrations of brain dopamine. The results will be relevant to the dopamine hypothesis of schizophrenia and may also implicate the PCP/NMDA system in the pathogenesis of schizophrenia. In the clinical part of the program, a metabolically defined "psychosis circuit" will be examined by 2-deoxyglucose (2DG) autoradiography in rats given the PCP agonist ketamine or CPP, a competitive NMDA antagonist, and by use of positron emission tomography (PET) scanning in schizophrenics and normals given ketamine. This study is intended to indicate additional brain areas which should be examined in rats to PCP-induced changes in dopamine and other monamine concentrations. In clinical studies during the last three years, neuropsychological testing of normals and schizophrenics will be conducted following dosing with ketamine. Cerebrospinal fluid dopamine and homovanillic acid will be measured in schizophrenic patients given ketamine.